An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania

Affiliations

• Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
• Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
• Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
• Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
• Department of Structural Biology and Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
• Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Blood Center of Zhejiang Province, Hangzhou, Zhejiang, China.
• Blood Center of Zhejiang Province, Hangzhou, Zhejiang, China.
• Stanford Blood Centre, Department of Pathology, Stanford University, Stanford, CA 94305, USA.
• Menzies School of Health Research, Charles Darwin University, Darwin, NT 0810, Australia; Department of Infectious Diseases, Royal Darwin Hospital, Casuarina, NT 0810, Australia.
• Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK.
• Institute of Social and Cultural Anthropology, School of Anthropology and Museum Ethnography, University of Oxford, Oxford OX3 7LF, UK.
• Papua New Guinea Institute of Medical Research, Post Office Box 60, Goroka, Papua New Guinea.
• Department of Biomolecular Engineering, UC Santa Cruz, Santa Cruz, CA 95064, USA.
• Advanced Genomics Unit, Center for Research and Advanced Studies (CINVESTAV), Irapuato 36821, Mexico.
• Jawun Research Centre, Central Queensland University, Cairns, QLD 4870, Australia.
• Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: jamie.rossjohn@monash.edu.
• Victorian Infectious Diseases Service, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3000, Australia; Department of Infectious Diseases, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3000, Australia. Electronic address: steven.tong@unimelb.edu.au.
• Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Electronic address: kkedz@unimelb.edu.au.
• Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Electronic address: agbrooks@unimelb.edu.au.
• Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Structural Biology and Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: paul.norman@cuanschutz.edu.

PMID:  39476840  DOI: 10.1016/j.cell.2024.10.005

Abstract

Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A∗24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1∗114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1∗114+NK cells from First Nations Australian donors are inhibited through binding HLA-A∗24:02. The KIR3DL1∗114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.

宿主免疫力的遗传变异影响着原住民可能经历的不成比例的传染病负担。多态人类白细胞抗原（HLA）Ⅰ类和杀伤细胞免疫球蛋白样受体（KIR）是自然杀伤细胞（NK）的关键调节因子，NK细胞介导早期感染控制。目前还不清楚这种变异如何影响它们在不同人群中的反应。我们的研究表明，在大洋洲的原住民中，通过积极的自然选择，HLA-A∗24:02 成为了抑制性 KIR3DL1 的主要配体。我们发现 KIR3DL1∗114 广泛分布于大洋洲并为大洋洲所独有，是源自古人类的等位基因系。来自澳大利亚原住民捐献者的 KIR3DL1∗114+NK 细胞通过结合 HLA-A∗24:02 受到抑制。KIR3DL1∗114 系是由残基 166 上的苯丙氨酸定义的。结构和结合研究表明，苯丙氨酸 166 与 HLA 肽复合物形成多种独特的接触，从而提高了亲和力和特异性。因此，评估免疫遗传变异及其对免疫的功能影响对于了解基于人群的疾病相关性至关重要。